Acute lung injury (ALI) is a significant cause of morbidity and mortality in the ICU. Pulmonary inflammation and increased vascular permeability are cardinal features of ALI, however the response to lung injury varies within the population and the mechanisms involved remain unclear. We hypothesize that there is a genetic predisposition for susceptibility to ALI. Using a model of intratracheal LPS and mechanical ventilation, we propose studies using consomic rat strains, highly inbred strains that have a single exogenous chromosome substituted into their genome, to identify first the chromosomes and then the genes that govern the ALI response. In Specific Aim #1, we will characterize the response to LPS and mechanical ventilation in the consomic parental strainis and determine strain-specific susceptibility to ALL In Specific Aim #2, we will use consomic backcrosses to identify the chromosomes and quantitative trait loci (QTL) for ALI. In Specific Aim #3, we wll use affymetrix cDNA microarrays to perform gene expression profiling to identify specific candidate genes within QTL region(s) involved in ALI. These studies will define the genomic response to ALI and may uncover novel targets which may lead to new therapeutic strategies in acute lung injury.